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Primary constitutional MLH1 epimutations: a focal epigenetic event
- Source :
- BRITISH JOURNAL OF CANCER, r-ISABIAL: Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante, Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL), Dipòsit Digital de la UB, Universidad de Barcelona, r-FISABIO: Repositorio Institucional de Producción Científica, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid, Consejería de Sanidad de la Comunidad de Madrid, r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante, instname, r-FISABIO. Repositorio Institucional de Producción Científica, British Journal of Cancer
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.
- Subjects :
- Male
0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Cancer Research
Locus (genetics)
Biology
Settore MED/03 - GENETICA MEDICA
MLH1
Article
Epigenesis, Genetic
Epigènesi
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Genetic Predisposition to Disease
Epigenetics
Allele
Promoter Regions, Genetic
neoplasms
Cancer
Epigenesis
Genetics
Base Sequence
Mutació (Biologia)
nutritional and metabolic diseases
Sequence Analysis, DNA
Methylation
DNA Methylation
Mutation (Biology)
medicine.disease
Colorectal Neoplasms, Hereditary Nonpolyposis
digestive system diseases
Lynch syndrome
030104 developmental biology
Haplotypes
Oncology
CpG site
030220 oncology & carcinogenesis
Mutation
CpG Islands
Female
Colorectal Neoplasms
MutL Protein Homolog 1
Subjects
Details
- ISSN :
- 15321827 and 00070920
- Volume :
- 119
- Database :
- OpenAIRE
- Journal :
- British Journal of Cancer
- Accession number :
- edsair.doi.dedup.....a9d6cba10643e6d937e24b3f421a91bc